What does a change in Hepatitis B (HBV) surface antigen (HBsAg) status from positive to negative indicate?

Interpretation of Hepatitis B Surface Antigen Status Change from Positive to Negative

A change in Hepatitis B surface antigen (HBsAg) status from positive to negative typically indicates resolution of HBV infection, which is associated with improved long-term outcomes including reduced risk of cirrhosis, hepatocellular carcinoma, and liver-related mortality.

Clinical Significance of HBsAg Clearance

HBsAg clearance represents a critical milestone in the natural history of chronic hepatitis B infection. This serological change has several important implications:

• Resolved infection: HBsAg loss with development of anti-HBs antibodies (seroconversion) indicates resolution of chronic HBV infection 1
• Improved prognosis: Patients who clear HBsAg have significantly better long-term outcomes with reduced risk of liver complications
• Reduced viral replication: HBsAg clearance is typically associated with undetectable or very low HBV DNA levels
• Decreased risk of transmission: Patients who clear HBsAg have minimal risk of transmitting the virus to others

Possible Scenarios for HBsAg Conversion from Positive to Negative

1. Natural Clearance

• Occurs spontaneously at a rate of approximately 1% per year in chronic carriers 2
• More common in patients with:
  • HBeAg-negative status
  • Low viral load (<2000 IU/ml)
  • Normal ALT levels
  • Longer duration of infection

2. Treatment-Induced Clearance

• May occur following antiviral therapy:
  • PEG-Interferon therapy: HBsAg loss rates of 3% at 6 months post-treatment, increasing to 9% at 3 years and 12% at 5 years 1
  • Nucleos(t)ide analogues: HBsAg loss is rare during the first 4-5 years of therapy 1

3. False Negative Result

• Possible explanations include:
  • HBV mutations affecting HBsAg detection (immune escape variants) 3
  • Additional N-linked glycosylation sites that mask immunogenic epitopes 3
  • Laboratory error or assay limitations

4. Occult HBV Infection

• Characterized by:
  • Negative HBsAg in serum
  • Detectable HBV DNA in liver or very low levels in serum
  • Usually positive for anti-HBc antibodies 4
  • May still pose risk for HBV reactivation during immunosuppression 1

Clinical Implications and Management

Confirmation Testing

1. Verify HBsAg clearance with repeat testing
2. Test for anti-HBs antibodies to confirm seroconversion
3. Check HBV DNA levels to ensure viral suppression
4. Test for anti-HBc to determine previous exposure status

Follow-up Based on Clinical Context

For patients with confirmed HBsAg clearance and seroconversion:

• Monitor liver function tests periodically
• Consider HCC surveillance if cirrhosis was present before HBsAg clearance
• No antiviral prophylaxis needed for most immunosuppressive therapies 5

For patients with HBsAg clearance without anti-HBs (occult HBV):

• Continue monitoring for potential reactivation
• Consider antiviral prophylaxis during immunosuppressive therapy, especially with:
  • Anti-CD20 monoclonal antibodies (e.g., rituximab)
  • High-dose corticosteroids
  • Stem cell transplantation 1, 5

Common Pitfalls to Avoid

1. Assuming complete cure: Despite HBsAg clearance, HBV DNA may persist in hepatocytes as cccDNA
2. Discontinuing surveillance: Patients with advanced fibrosis/cirrhosis should continue HCC surveillance
3. Ignoring reactivation risk: Patients who are HBsAg-negative but anti-HBc-positive remain at risk for reactivation during profound immunosuppression 1
4. Missing occult HBV infection: HBsAg negativity doesn't always represent viral clearance 4

Conclusion

HBsAg seroconversion from positive to negative generally represents a favorable outcome in the natural history of HBV infection. However, appropriate follow-up testing and monitoring are essential to confirm true viral clearance and assess the need for continued surveillance based on the patient's liver disease status and risk factors for reactivation.